Vaccination is a cost-effective means of promoting public health. It depends on the ability of the adaptive immune system, comprising T and B lymphocytes, to mount a rapid protective response to a second infection. Cytotoxic T lymphocytes which express the CD8 marker, are of vital importance in the response to many intracellular infectious agents. Our goal is to shed light on the factors that are involved in generating an effective CD8+ T cell response to pathogen and in promoting the differentiation of the primary effector cells into long-lived memory. It has recently become clear that helper T lymphocytes which express the CD4 marker, are critically involved in achieving this desired goal. Even in the face of infection with a virulent pathogenic virus or intracellular bacterium, the CD8 response requires the response of CD4+ T cells. This contribution may be via the activation of antigen presenting cells or via secretion of cytokines, such as IL-2, which may signal directly to the CD8+ T cells. CD4+ T cells are also required for the long term health and maintenance of CD8 memory cells once they are formed. Using infectious agents such as lymphocytic choriomeningitis virus and Listeria monocytogenes to infect mice we will probe the contribution of CD4+ T cells during the priming or vaccination stage and during memory maintenance. Specific Aim 1. To investigate the role of CD4+ T cells in maintaining the numbers, health and function of CD8+ memory T cells after the primary response is over. This entails asking which subset of CD4+ T cells provides the maintenance function, and its underlying basis. We have developed the helper-deficient, HD-/- mouse bearing a point mutation in the transcription factor Th-POK, as an ideal model in which to address these questions. Specific Aim 2. To investigate the factors, such as IL-2 signaling, that are relevant in programming the complete differentiation of pathogen-specific CD8+ T cells into memory cells capable of mounting a robust secondary response to pathogen rechallenge. The goal of vaccination is to generate a pool of memory lymphocytes specific for a pathogen which can protect us for a lifetime. Subsets of T lymphocytes, helpers and killers, must cooperate to achieve protection against many viral and bacterial infections. Our research will shed light on this cooperation for the promotion of long-lived protective immunity. Vaccination against infectious disease is the most cost-effective strategy in promoting human health. Our research is aimed at discovering the conditions that make long-term protection possible following vaccine delivery.